Carcinogenesis Advance Access originally published online on July 2, 2009
Carcinogenesis 2009 30(9):1591-1596; doi:10.1093/carcin/bgp159
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Genetic mapping of Mom5, a novel modifier of ApcMin-induced intestinal tumorigenesis
Department of Applied Chemistry and Microbiology (Nutrition), University of Helsinki, PO Box 66, Helsinki FIN-00014, Finland
1 Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, 985805 Nebraska Medical Center, Omaha, NE 68198, USA
2 Department of Biosciences and Nutrition, Karolinska Institute, NOVUM, S-14186 Huddinge, Sweden
3 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
* To whom correspondence should be addressed. Tel: +1 402 559 2456; Fax: +1 402 559 7328; Email: kagould{at}unmc.edu
Correspondence may also be addressed to Marja Mutanen. Tel: +358 9 191 58270; Fax: +358 9 191 58269; Email: marja.mutanen{at}helsinki.fi
The initial purpose of this study was to assess the role of estrogen receptor β (ERβ) in intestinal tumorigenesis by examining the effects of an ERβ knockout (ERβ–/–) on ApcMin mice. In order to accomplish this goal on a uniform genetic background, we were required to backcross the ERβ knockout from the 129P2 genetic background to the B6 genetic background for 10 generations. Midway through this process, we performed a test cross in which mice from the N5 backcross generation of the ERβ knockout strain were intercrossed with ApcMin/+ mice to obtain ApcMin/+ ERβ+/+, ApcMin/+ ERβ+/– and ApcMin/+ ERβ–/– mice. Intestinal tumorigenesis in the N5F2 mice was evaluated at 14 weeks of age. The analysis of the impact of ERβ in the N5 cross was complicated by segregating 129P2-derived alleles that affected tumor number and were unlinked to ERβ. Genetic linkage analysis of this cross permitted the localization of a single genetic modifier of tumor number in ApcMin/+ mice. This locus, Modifier of Min 5 (Mom5), maps to proximal mouse chromosome 5; the 129P2 allele of this locus is associated with a 50% reduction in mean intestinal tumor number. Through in silico analysis and confirmatory sequencing, we have identified the Rad50-interacting protein-1 gene as a strong candidate for Mom5.
Abbreviations: aa, amino acid; ERβ, estrogen receptor β; LOD, logarithm of the odds; MGI, mouse genome informatics; Mom, modifier of min; nt, nucleotide; QTL, quantitative trait locus; Rint-1, Rad50-interacting protein-1; SNP, single nucleotide polymorphism
These authors contributed equally to this work. Received November 6, 2008; revised June 15, 2009; accepted June 20, 2009.